Multiple Endocrine Neoplasia Type 1

Multiple endocrine neoplasia type 1 is an autosomal dominant syndrome caused by inactivating variants in the tumour suppressor gene MEN1, causing tumours of the parathyroids, pancreatic islets and anterior pituitary.

Prevalence is about 1 in 30,000. Penetrance is high: primary hyperparathyroidism occurs in about 90% by 50 years, pancreatic neuroendocrine tumours in 30 to 70%, and pituitary adenomas in 30 to 40%. Many patients also have adrenal cortical tumours, thymic and bronchial carcinoids, gastric neuroendocrine tumours, lipomas, facial angiofibromas, collagenomas and meningiomas.

The diagnosis is clinical (two of the three main tumours), familial (one main tumour plus a first degree relative) or genetic (a pathogenic MEN1 variant).

Pathophysiology.

MEN1 encodes menin, a nuclear scaffold protein involved in gene transcription and cell growth. A germline loss of one allele, then somatic loss of the second, leads to tumour formation (two hit model).

Hyperparathyroidism is typically multigland. Pancreatic tumours are often multiple and may be functioning (gastrinoma, insulinoma) or non-functioning.

• Hypercalcaemia: kidney stones, bone pain, fatigue, polyuria; often found at 20 to 30 years.
• Gastrinoma: refractory peptic ulcer, diarrhoea and reflux. Insulinoma: neuroglycopenic hypoglycaemia. Other functioning tumours: glucagonoma, VIPoma.
• Pituitary: galactorrhoea and amenorrhoea (prolactinoma), acromegaly, Cushing disease, visual field loss.
• Skin lesions and thymic or bronchial carcinoid symptoms.

Red flags.

• Hypercalcaemic crisis, severe hypoglycaemia or gastrointestinal bleeding.
• Rapid tumour growth, liver metastases or pituitary apoplexy.

• Hyperparathyroidism: albumin adjusted calcium and parathyroid hormone (multigland disease often in young patients).
• Pancreas: fasting gastrin (with gastric pH), glucose with insulin, C-peptide and proinsulin during a supervised fast, chromogranin A, pancreatic polypeptide, glucagon and vasoactive intestinal peptide.
• Pituitary: prolactin, IGF-1 and cortisol tests as indicated.
• MEN1 sequencing in index patients and relatives. Screening from childhood: calcium and parathyroid hormone from age 8; prolactin and IGF-1 from age 5; pancreatic MRI, CT or endoscopic ultrasound from age 10 yearly; pituitary MRI every 3 years; CT or MRI chest every 1 to 3 years for thymic and bronchial carcinoid.
• Adrenal imaging with hormone tests for any adrenal mass.

Differential diagnosis.

• Sporadic primary hyperparathyroidism, sporadic pancreatic neuroendocrine tumour and sporadic pituitary adenoma.
• Familial isolated hyperparathyroidism, hyperparathyroidism jaw tumour syndrome, MEN2A and MEN4 (CDKN1B).
• Familial hypocalciuric hypercalcaemia.

• Hyperparathyroidism: subtotal parathyroidectomy (3.5 glands) or total parathyroidectomy with autograft, with transcervical thymectomy, once biochemical hyperparathyroidism is established. Cinacalcet starting 30 mg twice daily (maximum 90 mg four times daily) if surgery is not possible.
• Gastrinoma: omeprazole 40 to 60 mg daily (titrated to control acid output) as first line. Surgery for non-functioning pancreatic tumours over 2 cm or growing, and for insulinoma (enucleation or distal pancreatectomy). Long acting somatostatin analogue (lanreotide 90 to 120 mg every 4 weeks) for functioning or progressive tumours. Hypoglycaemia from insulinoma: diazoxide 3 to 8 mg/kg daily in adults while awaiting surgery.
• Pituitary: prolactinoma with cabergoline 0.5 to 3 mg weekly; transsphenoidal surgery for others.
• Metastatic neuroendocrine disease: somatostatin analogues, peptide receptor radionuclide therapy, targeted drugs or chemotherapy.
• Genetic counselling: 50% risk for each child. Test relatives, and at risk carriers enter surveillance.

Special groups. Pregnancy: surgery for hyperparathyroidism in the second trimester if needed; gastrinoma control with proton pump inhibitor. Children: surveillance from age 5 to 10 years.

Monitoring. Calcium and parathyroid hormone yearly, pancreatic and pituitary imaging and hormones at the screening intervals given, and chest imaging every 1 to 3 years.

Referral and escalation. Endocrinology with endocrine surgery and a neuroendocrine tumour team; clinical genetics for family screening.